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1.
Nat Commun ; 10(1): 2884, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253780

RESUMO

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.


Assuntos
Ciliopatias/genética , Proteínas do Olho/genética , Predisposição Genética para Doença , Doenças Retinianas/genética , Elementos Alu/genética , Grupo com Ancestrais do Continente Asiático/genética , Genômica , Humanos , Japão , Mutação , Linhagem
2.
Pan Afr Med J ; 32: 84, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223375

RESUMO

Introduction: Sickle cell disease can result in visually threatening eye disease (proliferative sickle cell retinopathy). This can be prevented with timely eye screening. It is important for patients to understand their role. Our research is to determine the knowledge, beliefs and practices (KBP) regarding eye disease of Sickle Cell patients and the impact of genotype, demographic and socio-economic status. Methods: Cross-sectional study at the Sickle Cell Unit, Jamaica during May 2016. Consecutive non-pregnant adults (>18 years of age) attendees, who were not acutely unwell, were invited to participate. A 26-item single interviewer administered questionnaire was used to obtain socio-demographic data, highest level of education completed, employment status, sickle cell genotype, if known, frequency of clinic attendance and patients' knowledge, beliefs and practices. Ten of these were yes/no questions, whereas eight required that they choose correct answers from four choices. Results: One hundred subjects were recruited, 72% had homozygous SS disease. Their ages ranged from 18-63 years (mean 34.1 years, SD11.3). Fifty six percent were female. Most (75%) had achieved at least secondary education. The majority (62%) were unemployed. The mean belief score was 3.6/6(60%) and the mean knowledge and practice scores were 3.3/7(47%) and 2.2/5(44%) respectively. Milder genotypes had higher knowledge scores vs the more severe genotypes (4.0 vs 3.2, P=0.013). Only 28% had regular eye examinations; less than 50% had seen an ophthalmologist in the past year. Practice scores were higher in employed than in unemployed patients (2.6 vs 1.9, (P=0.04)). Employed patients were more likely than the unemployed to see their eye doctor for regular eye "examinations" (42.1% vs 19.4%, χ2=6.0, P=0.02). The practice and knowledge scores correlated (r2=0.363, P<0.001) and belief score (r2=0.304, P =0.002), except where 98% believed they should see an ophthalmologist annually, but only 42% did, and 21% had never. Conclusion: Knowledge scores were fair, however, the practice was not always in keeping with knowledge.


Assuntos
Anemia Falciforme/complicações , Conhecimentos, Atitudes e Prática em Saúde , Programas de Rastreamento/métodos , Doenças Retinianas/etiologia , Adolescente , Adulto , Anemia Falciforme/genética , Estudos Transversais , Emprego/estatística & dados numéricos , Feminino , Genótipo , Humanos , Jamaica , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto Jovem
3.
Prog Retin Eye Res ; 69: 137-158, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30982505

RESUMO

ELOngation of Very Long chain fatty acids-4 (ELOVL4) is an elongase responsible for the biosynthesis of very long chain (VLC, ≥C28) saturated (VLC-SFA) and polyunsaturated (VLC-PUFA) fatty acids in brain, retina, skin, Meibomian glands, and testes. Fascinatingly, different mutations in this gene have been reported to cause vastly different phenotypes in humans. Heterozygous inheritance of seven different mutations in the coding sequence and 5' untranslated region of ELOVL4 causes autosomal dominant Stargardt-like macular dystrophy (STGD3), while homozygous inheritance of three more mutant variants causes severe seizures with ichthyosis, hypertonia, and even death. Some recent studies have described heterozygous inheritance in yet another three mutant ELOVL4 variants, two that cause spinocerebellar ataxia-34 (SCA34) with erythrokeratodermia (EKV) and one that causes SCA34 without EKV. We identified the specific enzymatic reactions catalyzed by ELOVL4 and, using a variety of genetically engineered mouse models, have actively searched for the mechanisms by which ELOVL4 impacts neural function and health. In this review, we critically compare and contrast the various animal model and case studies involving ELOVL4 deficiency via either mutation or deletion, and the resulting consequences on neuronal health and function in both the retina and central nervous system.


Assuntos
Fenômenos Fisiológicos Celulares/fisiologia , Doenças do Sistema Nervoso Central/fisiopatologia , Proteínas do Olho/fisiologia , Mamíferos/fisiologia , Proteínas de Membrana/fisiologia , Células Fotorreceptoras de Vertebrados/fisiologia , Doenças Retinianas/fisiopatologia , Animais , Doenças do Sistema Nervoso Central/genética , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Doenças Retinianas/genética , Doenças Retinianas/metabolismo
4.
Invest Ophthalmol Vis Sci ; 60(4): 965-977, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30884523

RESUMO

Purpose: Retinal ischemia, a common cause of several vision-threatening diseases, contributes to the death of retinal neurons, particularly retinal ganglion cells (RGCs). Heat shock transcription factor 1 (HSF1), a stress-responsive protein, has been shown to be important in response to cellular stress stimuli, including ischemia. This study is to investigate whether HSF1 has a role in retinal neuronal injury in a mouse model of retinal ischemia-reperfusion (IR). Methods: IR was induced by inserting an infusion needle into the anterior chamber of the right eye and elevating a saline reservoir connected to the needle to raise the intraocular pressure to 110 mm Hg for 45 minutes. HSF1, Hsp70, molecules in the endoplasmic reticulum (ER) stress branches, tau phosphorylation, inflammatory molecules, and RGC injury were determined by immunohistochemistry, Western blot, or quantitative PCR. Results: HSF1 expression was significantly increased in the retina 6 hours after IR. Using our novel transgenic mice carrying full-length human HSF gene, we demonstrated that IR-induced retinal neuronal apoptosis and necroptosis were abrogated 12 hours after IR. RGCs and their function were preserved in the HSF1 transgenic mice 7 days after IR. Mechanistically, the beneficial effects of HSF1 may be mediated by its induction of chaperone protein Hsp70 and alleviation of ER stress, leading to decreased tau phosphorylation and attenuated inflammatory response 12 to 24 hours after IR. Conclusions: These data provide compelling evidence that HSF1 is neuroprotective against retinal IR injury, and boosting HSF1 expression may be a beneficial strategy to limit neuronal degeneration in retinal diseases.


Assuntos
Regulação da Expressão Gênica/fisiologia , Fatores de Transcrição de Choque Térmico/genética , Traumatismos do Nervo Óptico/genética , Traumatismo por Reperfusão/genética , Doenças Retinianas/genética , Animais , Western Blotting , Retículo Endoplasmático/metabolismo , Proteínas de Choque Térmico HSP70/genética , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Leucostasia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Compressão Nervosa , Neuroproteção/fisiologia , Traumatismos do Nervo Óptico/prevenção & controle , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Traumatismo por Reperfusão/prevenção & controle , Doenças Retinianas/prevenção & controle , Tomografia de Coerência Óptica , Proteínas tau/metabolismo
5.
BMC Evol Biol ; 19(1): 72, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30849938

RESUMO

BACKGROUND: Frizzled family members belong to G-protein coupled receptors and encode proteins accountable for cell signal transduction, cell proliferation and cell death. Members of Frizzled receptor family are considered to have critical roles in causing various forms of cancer, cardiac hypertrophy, familial exudative vitreoretinopathy (FEVR) and schizophrenia. RESULTS: This study investigates the evolutionary and structural aspects of Frizzled receptors, with particular focus on FEVR associated FZD4 gene. The phylogenetic tree topology suggests the diversification of Frizzled receptors at the root of metazoans history. Moreover, comparative structural data reveals that FEVR associated missense mutations in FZD4 effect the common protein region (amino acids 495-537) through a well-known phenomenon called epistasis. This critical protein region is present at the carboxyl-terminal domain and encompasses the K-T/S-XXX-W, a PDZ binding motif and S/T-X-V PDZ recognition motif. CONCLUSION: Taken together these results demonstrate that during the course of evolution, FZD4 has acquired new functions or epistasis via complex patter of gene duplications, sequence divergence and conformational remodeling. In particular, amino acids 495-537 at the C-terminus region of FZD4 protein might be crucial in its normal function and/or pathophysiology. This critical region of FZD4 protein may offer opportunities for the development of novel therapeutics approaches for human retinal vascular disease.


Assuntos
Evolução Molecular , Oftalmopatias Hereditárias/genética , Receptores Frizzled/química , Receptores Frizzled/genética , Doenças Retinianas/genética , Humanos , Proteínas Mutantes/química , Proteínas Mutantes/genética , Mutação de Sentido Incorreto/genética , Filogenia , Domínios Proteicos
6.
Mol Vis ; 25: 60-69, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820142

RESUMO

Purpose: To identify novel mutations in FZD4 and to investigate their pathogenicity in a cohort of Chinese patients with familial exudative vitreoretinopathy (FEVR). Methods: Next-generation sequencing was performed in patients with a clinical diagnosis of FEVR. Wide-field angiography was performed in probands and family members if available. Clinical data were collected from patient charts. The effect of the mutations in FZD4 on its biologic activity in the Norrin/ß-catenin signaling pathway was analyzed with the luciferase reporter assay. Results: Four novel mutations in FZD4 (c.1188_1192del/p.F396fs, c.1220delC/p.A407Vfs*24, c.905G>A/p.C302Y, c.1325T>A/p.V442E) were identified in four unrelated families. The mutations were not detected in 200 healthy individuals. The variability of the ocular phenotypes was not only observed in the probands and parents harboring the same mutation but also between two eyes in one individual. All four novel mutations introduced reduction in luciferase activity. Compared with the wild-type, the FZD4 level of the four mutants also decreased variably. Conclusions: Four novel mutations in FZD4 were identified in Chinese patients with FEVR. No correlation in the reduced luciferase activity and the ocular phenotype was observed in this study. This study further emphasized the complexity of the FEVR-causing machinery.


Assuntos
Oftalmopatias Hereditárias/genética , Proteínas do Olho/genética , Receptores Frizzled/genética , Mutação , Proteínas do Tecido Nervoso/genética , Doenças Retinianas/genética , beta Catenina/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , Estudos de Casos e Controles , Pré-Escolar , Oftalmopatias Hereditárias/diagnóstico por imagem , Oftalmopatias Hereditárias/etnologia , Oftalmopatias Hereditárias/patologia , Proteínas do Olho/metabolismo , Feminino , Angiofluoresceinografia , Receptores Frizzled/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Linhagem , Fenótipo , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/etnologia , Doenças Retinianas/patologia , Transdução de Sinais , beta Catenina/metabolismo
7.
Ophthalmic Surg Lasers Imaging Retina ; 50(2): 120-124, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30768221

RESUMO

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary ocular disorder characterized by incomplete or abnormal development of peripheral retinal vasculature. The genes responsible for this disorder are associated with the wingless-related integration site (Wnt) signaling pathway, a critical pathway for the development of normal retinal vasculature. A pathogenic variant in any one of these genes may disrupt retinal vasculogenesis. Furthermore, the type and number of pathogenic variants may influence the severity of disease and clinical course. Here, the authors identify a novel pathogenic variant in the NDP gene, not previously described in the literature. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:120-124.].


Assuntos
Oftalmopatias Hereditárias/genética , Proteínas do Olho/genética , Doenças Genéticas Ligadas ao Cromossomo X , Mutação , Proteínas do Tecido Nervoso/genética , Doenças Retinianas/genética , Pré-Escolar , Predisposição Genética para Doença , Humanos , Masculino , Linhagem , Penetrância
8.
Ophthalmic Surg Lasers Imaging Retina ; 50(2): e49-e51, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30768230

RESUMO

A 17-year-old boy, previously diagnosed with familial exudative vitreoretinopathy (FEVR) due to LRP5 mutation, complained of left eye decreased vision. Serial imaging by optical coherence tomography showed vitreomacular traction that progressed to lamellar macular hole (MH), and further evolved to full-thickness MH 3 weeks later. Visual acuity (VA) was 20/200. Pars plana vitrectomy with encircling buckle, internal limiting membrane peeling, and gas tamponade were performed. Three months postoperatively, VA had increased to 20/25 and the MH remained closed. This case illustrates how vitreomacular interface disorders may complicate FEVR, as exemplified for the first time in a case with LRP5 mutation. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e49-e51.].


Assuntos
Oftalmopatias Hereditárias/complicações , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Mutação , Doenças Retinianas/complicações , Perfurações Retinianas/etiologia , Adolescente , Oftalmopatias Hereditárias/genética , Humanos , Masculino , Doenças Retinianas/genética
9.
Value Health ; 22(2): 161-167, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30711060

RESUMO

OBJECTIVE: The gene therapy voretigene neparvovec (VN) is the first Food and Drug Administration-approved treatment for vision loss owing to the ultra-rare RPE65-mediated inherited retinal disorders. We modeled the cost-utility of VN compared with standard of care (SoC). STUDY DESIGN: A 2-state Markov model, alive and dead, with a lifetime horizon. METHODS: Visual acuity (VA) and visual field (VF) were tracked to model quality-adjusted life-years (QALYs). VN led to an improvement in VA and VF that we assumed was maintained for 10 years followed by a 10-year waning period. The cost of VN was $850 000, and other direct medical costs for depression and trauma were included for a US healthcare system perspective. A modified societal perspective also included direct nonmedical costs and indirect costs. RESULTS: VN provided an additional 1.3 QALYs over the remaining lifetime of an individual. The average total lifetime direct medical cost for individuals treated with VN was $1 039 000 compared with $213 400 for SoC, leading to an incremental cost-effectiveness ratio (ICER) of $643 800/QALY from the US healthcare system perspective. Direct nonmedical costs totalled $1 070 900 for VN and $1 203 300 for SoC, and indirect costs totalled $405 400 for VN and $482 900 for SoC, leading to an ICER of $480 100/QALY from the modified societal perspective. CONCLUSIONS: At the current price, VN was unlikely to reach traditional cost-effectiveness standards compared with SoC. VN has important implications for both development and pricing of future gene therapies; therefore clinical and economic analyses must be carefully considered.


Assuntos
Alelos , Análise Custo-Benefício , Terapia Genética/economia , Doenças Retinianas/economia , Doenças Retinianas/terapia , cis-trans-Isomerases/economia , Adolescente , Adulto , Idoso , Análise Custo-Benefício/métodos , Feminino , Terapia Genética/métodos , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Doenças Retinianas/genética , Transtornos da Visão/economia , Transtornos da Visão/genética , Transtornos da Visão/terapia , Adulto Jovem , cis-trans-Isomerases/administração & dosagem , cis-trans-Isomerases/genética
10.
Invest Ophthalmol Vis Sci ; 60(1): 93-97, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30640974

RESUMO

Purpose: Germline and somatic mutations in CTNNB1 have been found in different types of human diseases. This follow-up study aimed to identify causative germline mutations in CTNNB1 and their associated ocular phenotypes through a comparative analysis of whole-exome sequencing data. Methods: Annotated sequence variations in CTNNB1 were selected from in-house data from whole-exome sequencing of genomic DNA prepared from leucocytes of 3280 unrelated probands with different forms of eye diseases. Potentially pathogenic variants in CTNNB1 were analyzed by multistep bioinformatics analyses. Clinical data from probands with pathogenic variants in CTNNB1 were collected, and potential genotype-phenotype correlations were analyzed. Results: Eleven rare variants that potentially affect the coding regions of CTNNB1 were detected in 11 of the 3280 samples, and four variants were considered to be potentially pathogenic. All four mutations, namely, c.999delC (p.Tyr333*), c.1104delT (p.His369Thrfs*2), c.1738_1742delinsACA (p.Leu580Thrfs*28), and c.1867C>T (p.Gln623*), were heterozygotes and considered to have a germline origin. Three of the four mutations are de novo mutations, and the status of the remaining mutation is unavailable. All four probands had the same class of closely related ocular diseases: one proband had FEVR, and three probands had Norrie-like retinopathy. The molecular results indicated that three probands showed systemic anomalies, as demonstrated by a follow-up survey, but relevant information for the remaining proband was unavailable. Conclusions: The data suggest that germline truncating mutations in CTNNB1 cause autosomal dominant syndromic FEVR or Norrie disease. Patients with mutations in CTNNB1, KIF11, or NDP may have similar or overlapping phenotypes, but this phenomenon needs to be studied further.


Assuntos
Cegueira/congênito , Oftalmopatias Hereditárias/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação em Linhagem Germinativa , Doenças do Sistema Nervoso/genética , Degeneração Retiniana/genética , Doenças Retinianas/genética , Espasmos Infantis/genética , beta Catenina/genética , Cegueira/diagnóstico , Cegueira/genética , Análise Mutacional de DNA , Oftalmopatias Hereditárias/diagnóstico , Feminino , Angiofluoresceinografia , Seguimentos , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Lactente , Masculino , Doenças do Sistema Nervoso/diagnóstico , Fenótipo , Degeneração Retiniana/diagnóstico , Doenças Retinianas/diagnóstico , Espasmos Infantis/diagnóstico , Sequenciamento Completo do Genoma
11.
Hum Mol Genet ; 28(7): 1162-1172, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535121

RESUMO

The macula, located near the center of the retina in the human eye, is responsible for providing critical functions, such as central, sharp vision. Structural changes in the macula are associated with many ocular diseases, including age-related macular degeneration (AMD) and glaucoma. Although macular thickness is a highly heritable trait, there are no prior reported genome-wide association studies (GWASs) of it. Here we describe the first GWAS of macular thickness, which was measured by spectral-domain optical coherence tomography using 68 423 participants from the UK Biobank cohort. We identified 139 genetic loci associated with macular thickness at genome-wide significance (P < 5 × 10-8). The most significant loci were LINC00461 (P = 5.1 × 10-120), TSPAN10 (P = 1.2 × 10-118), RDH5 (P = 9.2 × 10-105) and SLC6A20 (P = 1.4 × 10-71). Results from gene expression demonstrated that these genes are highly expressed in the retina. Other hits included many previously reported AMD genes, such as NPLOC4 (P = 1.7 × 10-103), RAD51B (P = 9.1 × 10-14) and SLC16A8 (P = 1.7 × 10-8), further providing functional significance of the identified loci. Through cross-phenotype analysis, these genetic loci also exhibited pleiotropic effects with myopia, neurodegenerative diseases (e.g. Parkinson's disease, schizophrenia and Alzheimer's disease), cancer (e.g. breast, ovarian and lung cancers) and metabolic traits (e.g. body mass index, waist circumference and type 2 diabetes). Our findings provide the first insight into the genetic architecture of macular thickness and may further elucidate the pathogenesis of related ocular diseases, such as AMD.


Assuntos
Macula Lutea/patologia , Macula Lutea/fisiologia , Doenças Retinianas/genética , Idoso , Bancos de Espécimes Biológicos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Loci Gênicos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Glaucoma/genética , Humanos , Degeneração Macular/genética , Masculino , Pessoa de Meia-Idade , Miopia/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Retina/metabolismo , Retina/fisiopatologia , Reino Unido
14.
Methods Mol Biol ; 1834: 3-27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30324433

RESUMO

Inherited retinal diseases (IRDs) display a very high degree of clinical and genetic heterogeneity, which poses challenges in finding the underlying defects in known IRD-associated genes and in identifying novel IRD-associated genes. Knowledge on the molecular and clinical aspects of IRDs has increased tremendously in the last decade. Here, we outline the state-of-the-art techniques to find the causative genetic variants, with special attention for next-generation sequencing which can combine molecular diagnostics and retinal disease gene identification. An important aspect is the functional assessment of rare variants with RNA and protein effects which can only be predicted in silico. We therefore describe the in vitro assessment of putative splice defects in human embryonic kidney cells. In addition, we outline the use of stem cell technology to generate photoreceptor precursor cells from patients' somatic cells which can subsequently be used for RNA and protein studies. Finally, we outline the in silico methods to interpret the causality of variants associated with inherited retinal disease and the registry of these variants.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética , Animais , Mapeamento Cromossômico , Bases de Dados Genéticas , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Humanos , Padrões de Herança , Técnicas de Diagnóstico Molecular , Linhagem , Fenótipo , Sistema de Registros
15.
Methods Mol Biol ; 1834: 383-390, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30324456

RESUMO

Gene therapy holds promise for treating previously untreatable retinal disorders. The most promising approaches use gene transfer vectors derived from adeno-associated virus (AAV) to supplement a gene function in the affected cell type. One example is gene therapy for achromatopsia which affects daylight vision. In this case, recombinant AAV (rAAV) vectors are being developed to specifically target cone photoreceptors. Development of rAAV vectors could be facilitated by the use of in vitro models. In this chapter we provide a protocol which utilizes mouse 661W cells, an in vitro model of cone photoreceptors for evaluation of the transduction efficacy of rAAV vectors.


Assuntos
Dependovirus/genética , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos/genética , Retina/metabolismo , Animais , Linhagem Celular , Genes Reporter , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Humanos , Camundongos , Retina/citologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Doenças Retinianas/genética , Doenças Retinianas/terapia , Transdução Genética
16.
Acta Ophthalmol ; 97(3): 247-259, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30593719

RESUMO

PURPOSE: The aim of this study was to describe the genetic and clinical characteristics of Chinese patients with autosomal recessive bestrophinopathy (ARB). METHODS: This study presents a retrospective observational case series. Twenty-one ARB patients and 25 clinically healthy family members were recruited. The coding regions and adjacent intronic regions of BEST1 were analysed via Sanger sequencing. Clinical examinations, including ultrasound biomicroscopy, A-scan, optical coherence tomography, fundus autofluorescence, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA) and visual electrophysiology, were reviewed. RESULTS: Six novel mutations (c.380C>T, p.T127M; c.397A>G, p.N133D; c.500A>G, p.E167G; c.817G>A, p.V273M; c.174_176del, p.Q58del; and c.950_955del, p.S318_L319) and 8 previously reported mutations were identified. The p.R255W mutation had the highest frequency in our cohort. Twenty patients had serous retinal detachment with multifocal subretinal vitelliform deposits in the posterior poles. One patient exhibited chorioretinal atrophy. FFA revealed peripheral vascular leakage in 10 patients, and ICGA revealed hyperfluorescent spots in 8 patients. Visual electrophysiology was abnormal in all patients. Fifteen patients with angle closure (AC) or angle-closure glaucoma (ACG) had shallower anterior chambers and shorter axial lengths than the patients with open angle, contributing to their risk of developing AC/ACG. One patient developed AC during the 7-year follow-up period. The misdiagnosis and missed rates were 35.3% and 58.8%, respectively. CONCLUSION: The six novel mutations and high frequency of p.R255W suggest ethnical differences in the BEST1 mutation spectrum among Chinese patients. BEST1 gene screening and detailed clinical examinations help establishing a diagnosis of ARB. Clinical evaluations of the risk of developing AC/ACG are recommended for ARB patients.


Assuntos
Bestrofinas/genética , DNA/genética , Oftalmopatias Hereditárias/genética , Mutação , Doenças Retinianas/genética , Adolescente , Adulto , Bestrofinas/metabolismo , China/epidemiologia , Análise Mutacional de DNA , Oftalmopatias Hereditárias/epidemiologia , Oftalmopatias Hereditárias/metabolismo , Feminino , Angiofluoresceinografia , Fundo de Olho , Humanos , Incidência , Masculino , Linhagem , Retina/patologia , Doenças Retinianas/epidemiologia , Doenças Retinianas/metabolismo , Tomografia de Coerência Óptica , Adulto Jovem
18.
PLoS One ; 13(12): e0208897, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30571728

RESUMO

Retinal pigment epithelium (RPE) plays an essential role in maintaining retinal function, and its defect is thought to be critically implicated in various ocular disorders. This study demonstrated that the matricellular protein CCN5 was down-regulated in ARPE-19 cells treated with the pro-fibrotic agent transforming growth factor (TGF)-ß. A recombinant adenovirus expressing CCN5 (AdCCN5) was used to restore the level of CCN5 in these cells. AdCCN5 prevented TGF-ß-induced fibrotic changes, including disruption of tight junctions, up-regulation of mesenchymal marker proteins, and down-regulation of epithelial marker proteins. In addition, AdCCN5 prevented TGF-ß-induced functional defects, including increased migratory activity and reduced phagocytic activity. Notably, AdCCN5 reversed morphological and functional defects pre-established by TGF-ß prior to viral infection. The CCN5 level was down-regulated in RPE of 18-month-old Ccl2-/- mice, which exhibited retinal defects. Restoration of the CCN5 level via intravitreal injection of a recombinant adeno-associated virus expressing CCN5 (AAV9-CCN5) normalized the altered expression of mesenchymal, epithelial, and functional marker proteins, as assessed by western blotting and immunohistochemistry. Taken together, these data suggest that down-regulation of CCN5 is associated with fibrotic deformation of RPE under pathological conditions and that restoration of the CCN5 level effectively promotes recovery of deformed RPE.


Assuntos
Regulação para Baixo , Peptídeos e Proteínas de Sinalização Intracelular , Doenças Retinianas , Epitélio Pigmentado da Retina/metabolismo , Animais , Linhagem Celular , Dependovirus , Fibrose , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Knockout , Doenças Retinianas/genética , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Epitélio Pigmentado da Retina/patologia , Transdução Genética , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/genética
19.
Pharm Res ; 36(2): 29, 2018 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-30591984

RESUMO

A resurgence of interest and investment in the field of gene therapy, driven in large part by advances in viral vector technology, has recently culminated in United States Food and Drug Administration approval of the first gene therapy product targeting a disease caused by mutations in a single gene. This product, LUXTURNA™ (voretigene neparvovec-rzyl; Spark Therapeutics, Inc., Philadelphia, PA), delivers a normal copy of the RPE65 gene to retinal cells for the treatment of biallelic RPE65 mutation-associated retinal dystrophy, a blinding disease. Many additional gene therapy programs targeting both inherited retinal diseases and other ocular diseases are in development, owing to an improved understanding of the genetic basis of ocular disease and the unique properties of the ocular compartment that make it amenable to local gene therapy. Here we review the growing body of literature that describes both the design and development of ocular gene therapy products, with a particular emphasis on target and vector selection, and chemistry, manufacturing, and controls.


Assuntos
Dependovirus/química , Desenvolvimento de Medicamentos/métodos , Técnicas de Transferência de Genes/normas , Terapia Genética/métodos , Doenças Retinianas/terapia , Animais , Dependovirus/genética , Dependovirus/isolamento & purificação , Composição de Medicamentos , Vetores Genéticos/administração & dosagem , Humanos , Degeneração Macular/tratamento farmacológico , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/genética , Doenças Retinianas/patologia
20.
BMJ Case Rep ; 11(1)2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30567160

RESUMO

Inherited retinal venous beading is a rare retinal vascular disorder that is characterised by tortuosity and beading of the retinal veins. This can potentially lead to vision-threatening complications such as vitreous haemorrhage, macular hard exudation and ischaemia. We report a case of sporadic unilateral retinal venous beading in an 18-year-old white man who was referred by his optician following a routine eye examination. This malformation was unilateral and did not involve any other ocular structure. He had no associated ocular or systemic disorders. When last seen, he did not have any visual complications due to this vascular anomaly.


Assuntos
Doenças Retinianas/diagnóstico , Veia Retiniana/anormalidades , Adolescente , Diagnóstico Diferencial , Predisposição Genética para Doença , Humanos , Masculino , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/genética , Tomografia de Coerência Óptica
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